SOX11 contributes to the regulation of GDF5 in joint maintenance

Background: Individual skeletal elements of the vertebrate limbs arise through a segmentation process introducing joints in specific locations. However, the molecular pathways controlling joint formation and subsequent joint maintenance are largely unknown. In this study, we focused on SOX11, and its contribution to the regulation of GDF5, a secreted signal necessary for proper joint formation and postnatal joint homeostasis. Results: Sox11 is initially expressed broadly in the murine cartilage condensations at early stages of skeletal development, but its expression is specifically increased in the forming joint interzone as is forms. SOX11 overexpression can directly activate GDF5 expression both in vitro and in micromass cell cultures prepared from chick limb buds. Conserved SOX family binding sites are present in the 5’ UTR region of the GDF5 gene and we show SOX11 can specifically bind to one of them. While misexpression of Sox11 in developing chick limbs through RCAS virus infection does not induce Gdf5 expression in ectopic locations, it does enhance its expression. To explore the roles of Sox11 in joint homeostasis, we analyzed adult knee joints in an osteoarthritis mouse model where the medial meniscus and the medial collateral ligament were removed. We also analyzed knee joints from human subjects who underwent total knee replacement surgery. We find that SOX11 is mainly expressed in the weight-bearing areas of knee joints, and its expression is decreased in degraded cartilage during progression of knee osteoarthritis in both mice and humans. Conclusions: This work implicates SOX11 as a potential regulator of GDF5 expression in joint maintenance and suggests a possible role in the pathogenesis of osteoarthritis

Diabetic condition induces hypertrophy and vacuolization in glomerular parietal epithelial cells

Diabetic nephropathy (DN) is accompanied by characteristic changes in the glomerulus, but little is known about the effect of diabetes on parietal epithelial cells (PECs). In this study, a descriptive analysis of PECs was undertaken in diabetic db/db mice and in diabetic patients. PEC hypertrophy was significantly more prominent in diabetic mice than in nondiabetic mice, and this was evident even at the early stage. Additionally, the number of vacuoles in PECs was markedly increased in diabetic mice, suggesting the presence of cellular injury in PECs in DN. Although rare, binuclear cells were observed in mice with early diabetes. In cultured PECs, a high glucose condition, compared with normal glucose condition, induced cellular hypertrophy and apoptosis. Flow cytometry showed that some PECs in the G0 phase reentered the cell cycle but got arrested in the S phase. Finally, in human diabetic subjects, hypertrophy and vacuolization were observed in the PECs. Our data showed that PECs undergo substantial changes in DN and may participate in rearrangement for differentiation into podocytes

Protocol for a multicentre, prospective observational study of elective neck dissection for clinically node-negative oral tongue squamous cell carcinoma (END-TC study)

Introduction: In early-stage oral tongue squamous cell carcinoma (OTSCC), elective neck dissection (END) is recommended when occult lymph node metastasis is suspected; however, there is no unanimous consensus on the risks and benefits of END in such cases. The management of clinically node-negative (cN0) OTSCC remains controversial. This study, therefore, aimed to evaluate the efficacy of END and its impact on the quality of life (QoL) of patients with cN0 OTSCC. Methods and analysis: This is a prospective, multicentre, nonrandomised observational study. The choice of whether to perform END at the same time as resection of the primary tumour is based on institutional policy and patient preference. The primary endpoint of this study is 3-year overall survival. The secondary endpoint are 3-year disease-specific survival, 3-year relapse-free survival and the impact on patient QoL. Propensity score-matching analysis will be performed to reduce selection bias. Ethics and dissemination: This study was approved by the Clinical Research Review Board of the Nagasaki University. The protocol of this study was registered at the University Hospital Medical Information Network Clinical Trials Registry. The datasets generated during the current study will be available from the corresponding author on reasonable request. The results will be disseminated internationally, through scientific and professional conferences and in peer-reviewed medical journals

Protocol for a multicentre, prospective observational study of elective neck dissection for clinically node-negative oral tongue squamous cell carcinoma (END-TC study)

Introduction In early-stage oral tongue squamous cell carcinoma (OTSCC), elective neck dissection (END) is recommended when occult lymph node metastasis issuspected; however, there is no unanimous consensus on the risks and benefits of END in such cases. The management of clinically node-negative (cN0) OTSCCremains controversial. This study, therefore, aimed to evaluate the efficacy of END and its impact on the quality of life (QoL) of patients with cN0 OTSCC.Methods and analysis This is a prospective, multicentre, nonrandomised observational study. The choice of whether to perform END at the same time as resection of the primary tumour is based on institutional policy and patient preference. The primary endpoint of this study is 3-year overall survival. The secondary endpoints are3-year disease-specific survival, 3-year relapse-free survival and the impact on patient QoL. Propensity score-matching analysis will be performed to reduce selection bias.Ethics and dissemination This study was approved by the Clinical Research Review Board of the Nagasaki University. The protocol of this study was registered at the University Hospital Medical Information Network Clinical Trials Registry. The datasets generated during the current study will be available from the correspondingauthor on reasonable request. The results will be disseminated internationally, through scientific and professional conferences and in peer-reviewed medical journals

Observing change in pelagic animals as sampling methods shift: the case of Antarctic krill

Understanding and managing the response of marine ecosystems to human pressures including climate change requires reliable large-scale and multi-decadal information on the state of key populations. These populations include the pelagic animals that support ecosystem services including carbon export and fisheries. The use of research vessels to collect information using scientific nets and acoustics is being replaced with technologies such as autonomous moorings, gliders, and meta-genetics. Paradoxically, these newer methods sample pelagic populations at ever-smaller spatial scales, and ecological change might go undetected in the time needed to build up large-scale, long time series. These global-scale issues are epitomised by Antarctic krill (Euphausia superba), which is concentrated in rapidly warming areas, exports substantial quantities of carbon and supports an expanding fishery, but opinion is divided on how resilient their stocks are to climatic change. Based on a workshop of 137 krill experts we identify the challenges of observing climate change impacts with shifting sampling methods and suggest three tractable solutions. These are to: improve overlap and calibration of new with traditional methods; improve communication to harmonise, link and scale up the capacity of new but localised sampling programs; and expand opportunities from other research platforms and data sources, including the fishing industry. Contrasting evidence for both change and stability in krill stocks illustrates how the risks of false negative and false positive diagnoses of change are related to the temporal and spatial scale of sampling. Given the uncertainty about how krill are responding to rapid warming we recommend a shift towards a fishery management approach that prioritises monitoring of stock status and can adapt to variability and change

Observing change in pelagic animals as sampling methods shift: the case of Antarctic krill

Understanding and managing the response of marine ecosystems to human pressures including climate change requires reliable large-scale and multi-decadal information on the state of key populations. These populations include the pelagic animals that support ecosystem services including carbon export and fisheries. The use of research vessels to collect information using scientific nets and acoustics is being replaced with technologies such as autonomous moorings, gliders, and meta-genetics. Paradoxically, these newer methods sample pelagic populations at ever-smaller spatial scales, and ecological change might go undetected in the time needed to build up large-scale, long time series. These global-scale issues are epitomised by Antarctic krill (Euphausia superba), which is concentrated in rapidly warming areas, exports substantial quantities of carbon and supports an expanding fishery, but opinion is divided on how resilient their stocks are to climatic change. Based on a workshop of 137 krill experts we identify the challenges of observing climate change impacts with shifting sampling methods and suggest three tractable solutions. These are to: improve overlap and calibration of new with traditional methods; improve communication to harmonise, link and scale up the capacity of new but localised sampling programs; and expand opportunities from other research platforms and data sources, including the fishing industry. Contrasting evidence for both change and stability in krill stocks illustrates how the risks of false negative and false positive diagnoses of change are related to the temporal and spatial scale of sampling. Given the uncertainty about how krill are responding to rapid warming we recommend a shift towards a fishery management approach that prioritises monitoring of stock status and can adapt to variability and change

MLL fusion proteins link transcriptional coactivators to previously active CpG-rich promoters.

Mixed-lineage leukemia (MLL) maintains the expression of cellular memory genes during development, while leukemic MLL fusion proteins aberrantly maintain expression of hematopoietic stem cell program genes such as HOXA9 to cause leukemia. However, the molecular mechanism of gene activation is unclear. Here we show that only two functional modules are necessary and sufficient for target recognition: those that bind to non-methylated CpGs and di-/tri-methylated histone H3 lysine 36 (H3K36me2/3). An artificial protein composed of the two targeting modules and an interaction domain for AF4-family coactivators can functionally substitute for MLL fusion proteins. Because H3K36me2/3 markers are indicative of active transcription, MLL fusion proteins target previously active CpG-rich genes and activate transcription by recruiting coactivators thereto. Our results indicate that such chromatin context-dependent gene activation is the fundamental mechanism by which MLL fusion proteins maintain the expression of the cellular memory/hematopoietic stem cell program genes